Rapid and reversible methods for altering the expression level of endogenous proteins are not only indispensable tools for studying complex biological systems, but may potentially drive the development of new therapeutics for the treatment of many diseases. Techniques that manipulate protein expression and function by targeting DNA or mRNA have proven to be powerful tools, but are often plagued by problems such as lack of specificity, speed, reversibility and tunability1. Furthermore, their therapeutic use in treating human diseases may be stymied by the lack of an efficient systemic delivery system2.
To overcome shortcomings of DNA- and mRNA-based protein manipulations2, attempts have been made to harness cellular protein degradation systems to reduce levels of proteins-of-interest3-6. Many of these proposed systems require genetic manipulation of the proteins to facilitate their targeting and degradation via specific cellular protein degradation systems1.
Cell membrane penetrating domains (CMPDs) (also referred to as cell-penetrating peptides (CPPs) or protein transduction domains (PTDs)) are protein domains that mediate translocation across cellular membranes, such as the Tat protein from the HIV-1 virus and the Drosophila melanogaster Antennapedia homeodomain38,39,40.